Preclinical studies are uniform in demonstrating enlargement of small pre-existing collateral vessels in mice, rats and rabbits following acute-onset hindlimb ischemia. In the presence of competent endothelial function, improved collateral flow is sufficient to moderate hindlimb ischemia over the relatively short distances in these animals. The response in humans, however, is different. While significant increases in clinical indices of perfusion and exercise tolerance are uniformly observed in patients with intermittent claudication with prompting stimuli (e.g., daily walking), this cannot be ascribed to improved collateral blood flow in many of the clinical studies. Meaningful improvement in limb flow capacity requires extensive enlargement of these small collateral vessels, far greater than observed in small mammals, to compensate for the high conductance that normally supports flow to muscles at the long distances found in human legs. It is unknown whether the failure to observe significant increases in collateral blood flow in claudicant patients involved in exercise programs is due: 1) to an inability to develop sufficiently large collateral vessels due to an inadequate stimulus, or 2) to an inability to respond to an adequate stimulus that would normally prompt meaningful vessel enlargement. Further, it is unknown whether establishing a high arterial pressure (e.g., approximately 100 mmHg;increasing radial wall stress) within the large tortuous collateral conduits is sufficient to minimize regression of the vessel, in the absence of sustained arteriogenic stimuli that enlarged the collateral in the first place. Using a large mammal with femoral artery occlusion, we will: a) provide a commanding stimulus for collateral enlargement by increasing shear stress, using a unique arterial-venous shunt, and evaluate the competency of the endothelium to support collateral enlargement after inducing endothelial dysfunction by feeding the pigs an atherogenic diet, known to 'dull'endothelial responsiveness;b) assess the ability of exercise training to reverse the documented consequences of the HFC diet;and c) determine whether establishing a high luminal pressure is sufficient to retain large collateral vessels, once formed, in normal, atherogenic diet-fed, and exercise trained pigs. Instrumented limb blood flow (iliac a.), collateral network images, collateral blood flow (uspheres), in vitro function and morphology of collateral vessels, involvement of circulating vascular precursor cells, and functional capacity of the animals will be determined. Our evaluation of large-vessel collaterals should provide compelling evidence important in the management of claudicant patients with single-level, large-vessel proximal vascular lesions.